High sensitivty medical device and manufacturing thereof

ABSTRACT

This invention relates to a system and methods including their manufacturing technologies for enhanced sensing capability of one or more bioagents covering from HIV, Pathogens, virus, to cells detection. More particularly, this invention is related to HIV and pathogen diagnosis system and methods which may increase its sensitivity and may reduce the diagnosis time. Furthermore, the diagnosis system and method may be applicable to all early stage patients with various age groups, where early and accuracy in diagnosis, are required.

This is a continuation-in-part of U.S. Pat. No. 7,922,976 filed on Oct.23, 2006, and also application Ser. No. 13/041,433 filed on Mar. 6,2011, which is a divisional of application(s) Ser. No. 11/552,080 filedon Oct. 23, 2006

FIELD OF THE INVENTION

The present invention relates to high sensitivity sensor devices and itssignal processing circuits to detect the gas, biomolecules, cells, orbiochemical agents (altogether herein after mentioned as bio-agents).More specifically, this invention is related to sensor device comprisingwith at least one nano-chip for application in biomedical and industrialapplications. Furthermore, the continuation in part is more particularlyrelated to the system and method to diagnosis of virus, bacteria, cells,or infectious diseases, mainly found in body-fluidic system (e.g. fluid,blood) in human.

BACKGROUND OF THE INVENTION

The contents of all references, including articles, published patentapplications and patents, if referred to anywhere in this specificationare hereby incorporated by reference.

A large benefit of this sensor according to this invention, is thatthere can be several on a single wafer. It is a device able to measurechemical agent concentrations below part-per-billion (ppb) level andaccurately determine the biomolecule agent and volume of biologicalcells present in human body. There is no device in the state-of-art,which allows concurrent detection of a chemical agent, biomoleculeagent, and biological cell, all in a single system.

There are various kinds of sensor system. FIG. 1 shows a schematicrepresenting the prior art of a sensor system 1 to detect biologicalcells, biomolecule agents or chemical agents (hereafter mentioned asspecimen). The system 1 usually comprising with the sensor cell 2, powersupply 4, detector 6, and analyzer 8. The system 1 usually detects orsenses by detecting the electrical signal 10 induced due to absorptionof the specimen. Detector 6 will detect the output signal 10 and send tothe analyzer 8 to analyze the concentration of the specimen.

Several techniques can be found as the prior art for detectingconcentration of specimen (common term used hereafter separately forchemical, biomolecule agents, or biological cells). However, most ofthem are based on the standard electrical technique wherein only singlespecimen is considered to detect. In addition, most technique requireslong time in detection and/or not highly sensitive. The following, as apoint of reference, are some methods, which are already patented anddescribed as biosensors, used for detection of biological cells.

Peeters, in U.S. Pat. No. 6,325,904, (issued on Dec. 4, 2001), disclosesa nanosensor, using an array of electrodes at the atomic or nano scale(nanoelectrodes) level, formed by using specific receptors. Utilizingthe level of current flow while specific biological cells attacheddetermine the concentration. The drawbacks of such technique are: (i)requiring STM to position the receptor which time consuming fabricatingsuch sensor, (ii) requiring specific nano-scale level gap in betweenelectrodes containing receptor to conduct current, (iii) difficulties inmeasuring low current level (corresponding to low concentration) due touse of computer controlled technique, and (iv) requiring high power dueto using of computer controlled signal processing.

Bornhop, et al., in U.S. Pat. No. 6,809,828, (issued Oct. 26, 2004),discloses an sensor system for detecting proteins or DNA. Concentrationis estimated based on the fringe pattern, detected by the CCD camera inaddition with laser beam analyzer. Fringe pattern is usually dependingon the laser intensity and position of the CCD camera. The drawback ofthis technique are, (i) in accuracy in concentration measurement asfringe pattern is dependent on the laser intensity and position, (ii)difficulties in low level concentration measurement due to difficultiesin finding small changes in fringe pattern, and (iii) complete systembecoming bulky as CCD camera, position sensor, and laser beam analyzerare to be used.

Britton, Jr., et al., in U.S. Pat. No. 6,167,748, (issued Jan. 2, 2001),discloses a technique for detecting the glucose concentration in blood.Measurement of concentration is performed based on standard technique ofmeasuring the changes in capacitance. Technique uses cantilever coatedwith the receptor for absorbing the glucose. Main drawbacks are: (i)inability to detect low level concentration as very low changes in thecapacitive is difficult to measure, and (ii) difficulties of detectionof different kind of biological cell at the same time as each cantileverrequire different coating. Similar detection techniques can also befound in other patents such as U.S. Pat. No. 6,856,125, of Kermani(issued Feb. 15, 2005), U.S. Pat. No. 5,798,031 Charlton et al., (issuedAug. 25, 1998), U.S. Pat. No. 5,264,103 of Yoshioka et. al., (issuedNov. 23, 1993), and U.S. Pat. No. 5,120,420 of Nankai et. al., (issuedJun. 9, 1992), in all of which capacitive techniques are used to detectthe concentration. Chemical and biological sensors can be miniaturizedusing nanowires or carbon nanotubes. Continued advances in nanoscienceand nanotechnology require tiny sensors and devices to analyze smallsample sizes. The following is a discussion of the prior art in sensorfabrication.

After discussing the above issues pertaining to the state-of-artbiosensors, chemical sensors, and biomolecule sensors, and methods ofmaking them, we would now like to introduce a novel technique wheremultiple chemical agents can concurrently be detected in real time andthe information can quickly be transmitted to a main station anddisplayed. It is small in size, so the end user may carry it anywhere tomeasure the biological cell volume, protein, and biomolecule cells in amedical science application and is also able to do concurrent real timedetection of different kinds of chemical agents.

Despite the advances in therapeutics and improved public healthmeasures, infectious diseases still remain the major cause of morbidityand mortality in most parts of the world. Clinical syndromes are rarelyspecific for single pathogens, so multiplexed diagnostics provide gooddetection sensitivity, but are often slow, bulky, expensive, and relianton trained medical personnel. The development of handheld diagnosticsystems that can provide rapid diagnosis for multiplexed detection ofpathogens could significantly contribute to the prevention and treatmentof infectious diseases.

Similarly, that same multiplexed detection technology can be utilized todiagnose a single condition, such as HIV. Studies have shown that peoplenewly infected with HIV are most contagious because of the initial highviral loads. However, early stage detection is currently expensive andinaccurate. These detection systems have proven to be of limitedbenefit. Many potentially infected people cannot afford the laboratorytesting necessary, or cannot justify the cost due to the chances of amisdiagnosis. The multiplexed sensor described herein, however, will berelatively inexpensive, can be used by the average consumer, and willgive results quickly and accurately. There is thus a corresponding needto develop a universal diagnosis device, which can diagnosis multiplebio-agents (including infectious diseases, cells, DNA, RNA etc.),improve the effectiveness, sensitivity, and accuracy of diagnosis byreducing time and complexity, and by improving accuracy and consistencyof assessment of diagnosis studies. There is a clear role and need for asystem and methods, to improve sensitivity, accuracy, and diagnosis timeand facilitate more accurate and consistent diagnosis.

SUMMARY OF THE INVENTION

According to this current invention, it is an object to provide a sensorsystem comprising with a sensor more specifically relates to a novelnano-sensor. It is also object to provide the embodiments includingnovel methods, systems, devices, and apparatus for sensing one or morecharacteristics. One aspect of the present invention is a sensor, whichis capable of distinguishing between different molecular structures inchemical agents at the same time. It is also capable of distinguishingbetween different types of biomolecule agents or biological cellconcentrations. It is capable of detecting the concentration ofdifferent types of chemical agents, biomolecule agents, and biologicalcells.

This present sensor system is based on any type waveguide, including butnot limited to: the slab waveguide, the ridge waveguide, or a dielectricmaterials structure based waveguide. Its bottom clad (hereaftermentioned as substrate) can be formed using an array of variousdielectric materials, structured periodically, which can form thephotonic-band-gap (PBG). In waveguide, the guided light usually suffersradiation loss due to weak optical confinement; this happens when thestructure is not well optimized or the structural parameters areinterrupted. The sensor structure is optimized for a fixed wavelengthand is designed in such a way that the propagation loss is minimal.Alternatively, according to this invention, the sensor can also bedesigned to operate in broadband light operation. In that case, thewaveguide for nano-chip can be designed to operate multi-mode ofoperation.

This sensor detects the concentration of gases (that exist in air) basedon the change in the effective refractive index of the substrate causedwhen biomolecule gas/chemical agents fill the air (or receptor) spaces.The changes in the effective refractive index reduce the output opticalpower (measurable parameter). By comparing the output optical power withthe reference input optical power, the proposed nanosensor can detectthe biomolecule gas/chemical agent concentration in ppb levels.

It is noted here that the type of chemical agent/gas can be specified byusing a fixed receptor specifically made for absorbing said agent/gas.Also, the type of biomolecule agent or biological cell can be specifiedby using a fixed receptor to absorb the said biomolecule agent orbiological cell. The concentration of the agent/gas and the biomoleculeagent, and the volume of biological cells can be ascertained bymeasuring the output optical power, which is a function of the change ineffective refractive index and density. In this case, the detector willdetect the presence of a chemical agent/gas or a biomolecule agent or abiological cell. Then it will generate an electrical signal, which willbe processed through a processing circuit. After the processing circuit,a digital monitoring system will display the actual concentrationpresent via LED.

The materials used for the nanosensor and surrounding surfaces areselected based on their electrical and chemical properties. The PBGarrays may be included in a chamber, which can retain fluid forbiological applications; another set of arrays can be used for chemicalagents/gas detection. Several arrays may be used in a single chamber andseveral different chambers may be used in a single chip. Thus, onesystem may detect chemical agents/gas, biomolecule agents, andbiological cells.

This proposed PBG based nanosensor array and chamber as attached shouldbe separated from each other on a chip, so that each system worksproperly for each individual application. A Digital Signal Processing(DSP) function, Analog to Digital Converter (ADC), and microprocessorare provided to analyze signals from the nanosensors and/or do real timecalculations of the accurate values obtained from the nanosensor.

In some other embodiments a communication setup is used in order torelay the output values long distances. This communication setup isincluded to analyze the real time sensing values remotely.

Further embodiments, forms, features, objects and advantages of thepresent invention will be apparent from the following description.

Further, two specific embodiments for medical application are included.First, described is an embodiment for detecting pathogens, such asHepatitis B (HBV), through testing of blood, saliva, or other bodytissue. Second, described is an embodiment for detecting HIV in theblood.

BRIEF DESCRIPTION OF THE DRAWINGS

The features and advantages of the present invention will becomeapparent and may be better understood from the following detaileddescription of the system, taken in conjunction with the accompanyingdrawings, wherein

FIG. 1 is a schematic of sensor system in prior art.

FIG. 2 are the block diagrams representing the schematic of the sensorsystem for detecting the gas, bio-molecule, or biological cellconcentration.

FIG. 3A is a enlarged view of a nano-chip comprising with a waveguidebased on photonic bandgap (or photonic crystal) structures havingrectangular lattice, according to this invention, and FIG. 3B is across-section view across AA′ as shown in FIG. 3A.

FIG. 4 is a schematic diagram of a nano-chip comprising with a waveguidebased on photonic bandgap (or photonic crystal) structures havingtriangular lattice according to this invention, and FIG. 4B is across-section view across BB′ as shown in FIG. 4A.

FIG. 5 is a schematic diagram of a nano-chip comprising with a waveguidebased on photonic bandgap (or photonic crystal) structures havingrectangular lattice, according to this invention, and FIG. 5B is across-section view across CC′ as shown in FIG. 5A, where the PBG isrectangular in shape with holes and a slab waveguide is used.

FIG. 6 is a schematic diagram of a nano-chip comprising with a waveguidebased on photonic bandgap (or photonic crystal) structures havingdefects and rectangular lattice, according to this invention, and FIG.6B is a cross-section view across DD′ as shown in FIG. 6A.

FIG. 7 is a schematic diagram of a nano-chip comprising with a waveguidebased on photonic bandgap (or photonic crystal) structures havingdefects, according to this invention.

FIG. 8 is schematic of interconnection between the nano-chip and itsdetector.

FIG. 9 is the block diagram representing an example of an electricalsignal processing circuit to detect the specimen, according to thisinvention.

FIG. 10A is a schematic representing a integration circuit unit forsignal pre-processing, a part of processing circuit, as shown in FIG. 9,according to this invention, and FIGS. 10B and 10C are output signals atpoints A and B, shown in FIG. 10A.

FIG. 11A is a schematic representing a filter circuit unit, a part ofsignal post processing, according to this invention, and FIGS. 11B and11C are output signals showing with capture points, with and withoutspecimen absorption.

FIG. 12 is a schematic representing a read-out circuit used to store thereference signal.

FIG. 13 is a block diagrams representing monitoring unit according tothis invention.

FIG. 14 is a schematic representing an alternative read-out circuit tostore the reference signal.

FIG. 15 is a schematic showing an example of a complete sensor devicefor multiple specimens' detection, according to this invention.

FIG. 16 is a schematic showing an example of a complete sensor device,packaged in small form-factor, according to this invention.

FIG. 17 is a schematic showing the manufacturing process for thenanochip, according to this invention.

FIG. 18 is a schematic showing an embodiment including a bloodfiltration system on a disposable test strip, which is connectable tothe diagnosis device, according to this invention.

FIG. 19 is a detailed illustration of a potential embodiment, based onthe schematic shown in FIG. 18, according to this invention

FIG. 20A is a schematic showing a illustrative diagram of thefunctionality of HIV-1 RNA^(TAT) aptamers as bioreceptors for HIV-1 TATprotein binding and can be used in this biosensor, for diagnosis of HIV,according to this invention.

FIG. 20B is a schematic showing a Illustrative diagram of thefunctionality of HIV-1 antigens as bioreceptors for binding withantibodies for HIV diagnosis

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Some embodiments of the current invention are discussed in detail below.In describing embodiments, specific terminology is employed for the sakeof clarity. However, the invention is not intended to be limited to thespecific terminology so selected. A person skilled in the relevant artwill recognize that other equivalent components can be employed andother methods developed without departing from the broad concepts of thecurrent invention.

In the following detailed description of the preferred embodiments,reference is made to the accompanying drawings, which form a parthereof, and in which is shown by way of illustration specific preferredembodiments in which the inventions may be practiced. These embodimentsare described in sufficient detail to enable those skilled in the art topractice the invention and it is to be understood that other embodimentsmay be utilized. The following detailed description is, therefore, notto be taken in a limiting sense, and the scope of the present inventionis defined only by the appended claims.

According to this current invention, it is our objective to provide asensing device comprising with nano-sensor and its signal processingcircuit which can have the significantly high sensitivity. The sensordevice detects the specimen concentration based on the principle ofoptics. Using of the nano-sensor and signal processing circuit,according to this invention, high sensitivity can be achieved. Detectionis mainly based on detecting the difference in intensity of opticalsignal obtained after specimen absorb in the receptor and converting toelectrical signal and their arithmetic processing to achieve significanthigh sensitivity.

FIG. 2 shows a block diagram of the system according to this invention.In block diagram 22, input optical signal 14 is generated from a laser12 having a wavelength ranging from ultra-violet to infrared. The signal14 will pass through the nano-chip 16(a, b, c, d, e). For a unique andoptimized design (with no presence of specimen or sample) intensity ofoutput optical power 18 from the nano-chip 16(a, b, c, d, e) can be sameas that of input optical power 14. This means that the coupling lossthough the nano-chip is be zero. The presence of the specimen or sampleinside of the nano-chip 16(a, b, c, d, e) will cause a reduction in theoutput optical power 18, detected by the detector 20. The reduction inoutput optical power 18, if any, is due to the change in the refractiveindex of the receptors with and without absorption of the specimen. Thereceptor is usually contained in the nano-chip 16(a, b, c, d, e),explained later in FIG. 3. The detector 20 is used to convert theoptical signal 18 into an electrical signal 26 and the said electricalsignal 26 is processed through the processing circuit 28, explainedlater in detail in FIGS. 9-13. The resultant signals 29(a) and 29(b)from said processing circuit 28 is passed through digital signalprocessing circuit (DSP) 30 where related arithmetic function can beperformed to monitor actual concentration of the specimen in real time.Details of the DSP circuits are provided in FIG. 13.

According to this invention, the processing circuit can be made inhybrid using different functional chips or using single chip having allfunctions, and those can be fabricated from 350 nm or less geometry. Thedetector can be chosen based on the wavelength of the light to be usedin the system 22. For example, if the wavelength is selected in visibleregion, the silicon-detector can be used in system 22. On the otherhands, if the wavelength of near infrared is chosen, then the detectormade from III-V compound semiconductor is required for having highersensitivity.

According to this invention, the system 22 can be miniaturized into avery small package (e.g. less than 1 to 0.5 inches in dimension). Themain advantage of the system 22, according to this invention, is thatonly the power of output optical signal 18 needs to be known in order toascertain the concentration. In system 22, very little power will beabsorbed by the nano-chip and this is based on the percentage of therefractive index change. The system 22 has two parts: the first is a‘detection part’ comprising of laser 12, nano-chip 16(a, b, c, d, e),and the detector 20; the second is an ‘analyzing part’, comprising ofsignal processing circuits 28 and 30.

According to this invention, different nano-chips 16(a, b, c, d, e) areexplained in FIGS. 3 to 7. FIG. 3A shows a schematic, representing theenlarge view of a nano-chip 16 a and FIG. 3B is the cross-sectional viewof section AA′, as shown in FIG. 3A. According to this invention, thenano-chip 16 a can be made from photonic crystal comprising ofdielectric rods 32 arranged periodically in hollow clad 33 (hereafter wedefine clad as a substrate with a refractive index ‘n_(sub)’) to form aphotonic-band-gap (PBG) and/or photonics-crystal structures, havingrectangular lattice 34. The nano-chip 16 a has waveguide structurehaving core 35 having refractive index of ‘n_(core)’. Each rod 32 has aradius of ‘r’ (from 0.1 μm to 0.3 μm or may be in different sizedepending on the design) and they are separated by a distance ‘a’ (knownas pitch or lattice constant) 36, which is equal to or greater than‘2r’. Receptors 40 can be placed in-between the spaces of the rods 32 inhollow clad 33.

Receptors 40, shown in FIG. 3 (For example: ACh—Acetylcholine covers fornerve agents, AH—Aromatic Hydrocarbon, etc.) can be used inside thenano-chip 16(a, b, c, d, e). Here, receptor 40 is used to detect thetype of specimen and they absorb/interact with the respective specimen(e.g. biomolecule or chemical agents or biological cell) present inbetween the spaces of the dielectric rods.

Each rod 32 has a refractive index ‘n’ which can be either equal to‘n_(core)’ or refractive index ‘n’ can be greater or less than the corerefractive index n_(core)’. Optical signal input 14 to nano-chip 16 a istransmitted through the core 35. Based on the absorption of the specimen(not shown here) by the receptor 40 located in the space between therods 32, the refractive index of the substrate ‘n_(sub)’ in combinationwith hollow clad 33 and receptor 40 is changed to ‘n_(eff)’, theeffective refractive index, and as a result, the power output opticalsignal 18 is reduced. The concentration of the specimen can bedetermined by calculating the change of the refractive index of thereceptors 40 after and before of absorption of the specimen and thechanges in power of the optical signal 18 with respect to input opticalsignal 14. Changes in power of optical signals between 14 and 18 can bedetermined by the power-factor, which is defined as the ratio of theoutput optical power over the input optical power. According to thisinvention, the main advantage is that by knowing the power factor, thechanges in refractive index and also the concentration of the specimencan be determined. By calculating the power-factor, this proposed sensorwould give the real-time concentration of the specimen.

Nano-chip 16 a used for system 22 is based on photonic-crystal and theyare having different structures. Two-dimensional (2-D) orthree-dimensional (3-D) photonic crystal can be used to fabricate thenano-chip 16 a. In FIG. 3A, the photonic crystal is formed based on thedielectric rods 32. Alternatively, the photonic crystal can be also madefrom holes, periodically arranged inside the dielectric materials.

FIG. 4A shows a schematic, representing the enlarge view of analternative nano-chip 16 b and FIG. 4B is the cross-sectional view ofsection BB′, as shown in FIG. 4A, according to this invention whereinthe same numerals in FIGS. 4A and 4B represent the same parts in FIGS.3A and 38, so that repeated explanation is omitted here. Only differencein FIGS. 4A and 4B as compared with FIGS. 3A and 3B is that the photoniccrystal is made from the dielectric rods 32 placed in hollow clad 33,wherein the rods 32 is having the triangular lattice 44.

FIG. 5A shows a schematic, representing the enlarge view of analternative nano-chip 16 c and FIG. 5B is the cross-sectional view ofsection CC′, as shown in FIG. 5A, according to this invention, whereinthe same numerals in FIGS. 5A and 5B represent the same parts in FIGS.3A, 3B 4A, and 4B, so that repeated explanation is omitted here. Themain difference in FIGS. 5A and 5B as compared with FIGS. 3A, 3B, 4A,and 4B is that the photonic crystal is based on the holes 51periodically arranged inside the slab acting as the clad 53, wherein theholes 51 are filled up with the receptors 40 and also the holes 51 ishaving the rectangular shaped lattice 50. According to this invention,optical signal 14 is guided through the slab-type waveguide 48 locatedinside slab (or clad) 53. Each hole 51 in nano-chip 16 c has a radius of‘r’ and they are separated by a distance ‘a’ (also known as latticeconstant) 52. Inside each hole, receptors 40 are present toabsorb/interact with the specimen/sample. 54 shows the cross sectionalview of this nano-chip 16 c. The nano-chip can also be designed bymaking holes in a triangular shape. Specification of the radii of theholes ‘r’ and lattice constant ‘a’ 52 will be optimized depending on thesize of the nano-chip 16 c.

FIG. 6A shows a schematic, representing the enlarge view of analternative nano-chip 16 d and FIG. 6B is the cross-sectional view ofsection DD′, as shown in FIG. 6A, according to this invention, whereinthe same numerals in FIGS. 6A and 6B represent the same parts in FIGS.3A, 3B 4A, 4B, 5A, and 5B, so that repeated explanation is omitted here.The main difference in FIGS. 6A and 6B as compared with FIGS. 5A and 5Bis that the nano-chip 16 d is also based on photonic crystal, butcomprising with defects 56 in the holes periodically structure in thecore 57. “Defects in the holes,” means that the diameter of some holesis bigger than the diameter of the ‘regular’ holes, all structuredperiodically. According to this invention, the defects 56 can also befilled with the receptor 40 and they can be created either using ofholes 56, as shown in FIGS. 6A and 6B, or using of the solid rods havingspecific radius (not shown here).

FIG. 7 shows a schematic, representing the enlarge view of analternative nano-chip 16 e, according to this invention, wherein thesame numerals in FIG. 7 represent the same parts in FIGS. 6A and 6B, sothat repeated explanation is omitted here. The main difference in FIG. 7as compared with FIGS. 6A and 6B is that the nano-chip 16 e is based onthe solid slab 58 acting as the clad and the core 59 to guide theoptical signal 14, comprises with holes as defects 60 arrangedperiodically inside core 59 forming photonic band gap structure. Asmentioned earlier, any type of specimen can be detected and theirconcentration can be known after processing the output optical signal 18from nanochip. Type and concentration of any specimen such as gases,biomolecules, or any biological cells can be detected by making them toabsorb on corresponding receptor 40 to be used in the holes 60.

The nano-chip 16(a, b, c, d, and e), can be fabricated usingdielectrics, semiconductor, or polymer materials. The dielectricmaterial can cover all kind of materials having dielectric or opticalproperties (e.g. refractive index), such as glass, quartz, polymer etc.According to this invention, alternatively, the nano-chip can also befabricated from semiconductor materials, such as Si, GaAs, InP, GaN,SiC, diamond, graphite etc. which can be fabricated using standard's ICfabrication technology. This nano-chip itself can be from rigid orflexible substrate.

The nano-chip can be fabricated by standard dry or wet etching to formthe holes or rods embedded inside the solid or hollow substrate.Alternatively, this can also be fabricated using spin-coated polymer orpreformed polymer. The low shrinkage in polymerization and thetransparency of the synthesized polyurethane can also be used infabrication of infiltrated inverse opal elastomeric photonic-crystalstructures for the nano-chip according to this invention. The nano-chip16(a, b, c, d, and e) can have high-symmetry cross-sections and canallow integrated optical networks to be formed by only placing eitherthe rods in air or air cylinders in the dielectric. The nano-chip 16 canalso be fabricated in multiple layers by stacking the slabs on top ofone another, separating them with a separator. According to thisinvention, the nano-chip 16(a, b, c, d, and e) and surrounding circuitrycan be made into the single chips using today's IC process technology.

The specific specimen can be detected using the nanochip with specificreceptor. For example, Avidin Biotin which is the most common uses as areceptor for glycoconjugate analysis and DNA detection systems, can beused also as the receptor 40 in the nanochip 16(a,b,c,d, and e). Singlereceptor agent or solution linked with other molecule acting as thereceptor (for the specific specimen) can also be used as receptor 40.For example, Dimethylsulfoxide (DMSO) solution containing 4 mg/ml of theheterobifunctional linker molecule succinimidyl-6-hexanoate(biotinamido) for a 1 hour at room temperature and the resultantreceptor can be used as receptor 40 for DNA detection. According to thisinvention, the receptor 40 can be gel-type, solid, or solution based.

A derivation is given here for the generalized analytical equation forthe nanochip described earlier in FIGS. 3 to 7. This derivation helps tounderstand the insight of this current invention for high sensitivitysensor device. For simplicity in derivation, nano-chip, as shown in FIG.7, consisting of a ridge waveguide in the core formed by periodicallystructured PBG, is considered as the example and this nanochip can beconsidered as a linear system. The waveguide structure is considered tobe optimized for providing almost same output optical power 18 for thespecific wavelength of the optical input 14. By knowing the outputoptical power the concentration of the specimen (e.g. biological cells,industrial gas, or biological cell agents) can be detected. According tothis current invention, nano-chip is considered to be formed based onthe 2-D photonic crystals. Related generalized equations, required fordetermining specimen concentration is described herewith. Noted herethat type of specimen can be known from the specific receptor 40, asexplained earlier. The specific receptor is used for specific link orbond.

According to this invention, the waveguide structure is to be designedin such a way that maximum optical power for optical signal 18 isachieved (or very to optical power of input optical signal 14), and thatcondition (or optical power) can be considered as the reference (i.e.with specimen present) in the holes.

The symbol used in derivation is summarized in Table I.

TABLE I Description of the symbols used in derivation ParameterDescription n_(cref) Reference refractive index of the core n_(ceff)Effective (new) refractive index of the core N Gladstone-Dale constantP_(in) Input optical Power P_(out) Output Optical Power Power Factor =P_(out)/P_(in) Ratio of output optical power and input optical powerρ_(ref) Reference density (air or filled with receptor) ρ_(new) Newdensity after specimen absorbed Δ_(ρ) Change in density

For linear system with ridge waveguide, Power Factor, ratio of outputoptical power (P_(out)) to input optical power can be derived asfollows:

$\begin{matrix}{{{Power}\mspace{14mu} {Factor}} = {\frac{P_{out}}{P_{in}} = {1 - \frac{n_{cref}^{2} - n_{ceff}^{2}}{n_{cref}^{2} - n_{clad}^{2}}}}} & \left( {1\; a} \right)\end{matrix}$

Where, n_(cref) is the reference refractive index of the core withoptimized waveguide. n_(ceff) is the effective refractive index of thecore and n_(clad) is the refractive index of the clad. From Eq. (1a),coupling loss can be written as

Coupling Loss=1−Power Factor  (1b)

Where, Coupling Loss is,

$\begin{matrix}{{{Coupling}\mspace{14mu} {Loss}} = \frac{n_{cref}^{2} - n_{ceff}^{2}}{n_{cref}^{2} - n_{clad}^{2}}} & \left( {1\; c} \right)\end{matrix}$

From Eq. (1a), relationship between Power Factor and density of the gascan be derived. The relationship between n_(cref), reference corerefractive index (with no gas condition) and ρ_(ref), reference densityof receptor can be expressed by using of Gladstone-Dale relationship,

n _(cref)−1=ρ_(ref) ×N  (2)

where, N is the Gladstone-Dale constant

As mentioned earlier, after sensing the gas, the density of the receptorρ_(new), after absorbing the gas which changes the effective refractiveindex of the substrate, nceff (mentioned as new core effectiverefractive index). Similarly, nceff relates with ρ_(new) as,

n _(ceff)−1=ρ_(new) ×N  (3)

From Eqs. (2) and (3), this following expression can be derived:

$\begin{matrix}{\frac{n_{cref} - 1}{n_{ceff} - 1} = \frac{\rho_{ref}{XN}}{\rho_{eff}{XN}}} & (4)\end{matrix}$

From Eq. (4) n_(ceff) expression can be derived as:

$\begin{matrix}{n_{ceff} = {1 + {\frac{\left( {n_{cref} - 1} \right)}{\rho_{ref}}\rho_{new}}}} & \left( {5\; a} \right)\end{matrix}$

After substituting Eq. (5a) into Eq. (1a), we get the new density asfollows:

$\begin{matrix}{\rho_{new} = \frac{\left\lbrack {\sqrt{n_{cref}^{2} - {\left( {1 - {{Power}\mspace{14mu} {Factor}}} \right)\left( {n_{cref}^{2} - n_{clad}^{2}} \right)}} - 1} \right\rbrack \rho_{ref}}{\left( {n_{cref} - 1} \right)}} & \left( {5\; b} \right)\end{matrix}$

Changes in density ρ can be expressed as,

Δρ=ρ_(new)−ρ_(ref)  (6)

Concentration of the bio-agent in ppb, which is a function of themolecular weight and Δp, and ppb can be written as

$\begin{matrix}{{ppb} = \frac{\Delta \; \rho \times 0.02}{{Molecular}\mspace{14mu} {Weight}}} & (7)\end{matrix}$

After substituting Eq. (6) into Eq. (7), the concentration of gas in ppbcan be expressed as:

$\begin{matrix}{{ppb} = {\left( {\rho_{new} - \rho_{ref}} \right)\frac{0.02}{{Molecular}\mspace{14mu} {Weight}}}} & (8)\end{matrix}$

Now substitute value of ρ_(new) in Eq. (8) and we can derive ppb, whichis

$\begin{matrix}{{ppb} = {\left\lbrack {\frac{\left\lbrack {\sqrt{n_{cref}^{2} - {\left( {1 - {{Power}\mspace{14mu} {Factor}}} \right)\left( {n_{cref}^{2} - n_{clad}^{2}} \right)}} - 1} \right\rbrack \rho_{ref}}{\left( {n_{cref} - 1} \right)} - \rho_{ref}} \right\rbrack \times \frac{0.02}{{Molecular}\mspace{14mu} {Weight}}}} & (9)\end{matrix}$

Alternatively, particularly for medical diagnosis purposes, the abovecalculations can instead be done to allow for sensing targetbiomolecules in a non-gaseous form, and at even lower concentrations,such as parts per billion (ppb).

$\begin{matrix}{{ppb} = {\left\lbrack {\frac{\left\lbrack {\sqrt{n_{cref}^{2} - {\left( {1 - {{Power}\mspace{14mu} {Factor}}} \right)\left( {n_{cref}^{2} - n_{clad}^{2}} \right)}} - 1} \right\rbrack \rho_{ref}}{\left( {n_{cref} - 1} \right)} - \rho_{ref}} \right\rbrack \times \frac{(0.02)}{{Molecular}\mspace{14mu} {Weight}}}} & (10)\end{matrix}$

Potentially, biomolecules might be detectable in ppb or even furtherlower concentrations, such as parts per trillion or even quadrillion.

According to this invention, by knowing the power factor (which is ratioof power of optical out 18 to power of optical in 12 to and from thenanochip 16, respectively to the optical input), and appropriatearithmetic signal processing, the concentration of the specimen can beknown. According to this invention, the gas is considered, it can bealso be used for biomolecule gas, or biomolecule cells, if correspondingreceptor is used. From FIGS. 8 to 14, the signal processing fordetecting small change in power factor are given. FIGS. 15 and 16explain the sensor device according to this invention.

FIG. 8 shows a schematic representing the nano-chip and its detectionblock diagram according to this invention wherein same numeralsrepresents the similar parts shown in FIGS. 2, 3, 4, 5, 6, and 7, sothat similar explanation is omitted here. In FIG. 8, the optical signal18 from nano-chip 16(a, b, c, d, or e) is detected by the (optical)detector 61 to convert into corresponding electrical signal 26. Thedetector 61 should be selected based on the wavelength of the light usedin the nano-chip. For example, for visible wavelength, Si-basedphotodetector can be used which can provide quantum efficiency close to100% over visible wavelength. For Near infrared wavelength, III-Vcompound semiconductor based detector can be used.

Photodiodes can be used in either zero bias or reverse bias. In zerobias, light falling on the diode causes a voltage to develop across thedevice, which leads to current flowing in the forward bias direction.Diodes usually have extremely high resistance when reverse biased. Thisresistance is reduced when light of an appropriate wavelength incidentonto the junction. Hence, a reverse biased diode can be used to generatethe photo current. Circuit with reverse-biased detector is moresensitive to light than one with zero-biased detector.

The detector can be p-n junction based detector or avalanche photodiode(APD) detector, According to this invention; both type photodetector(p-n or APD) can be used. Only difference is there operational voltage.For example, APD requires high voltage and on the other hands, p-njunction requires low voltage. By using of APD, according to thisinvention, single photon level difference in optical power between inputto nano-chip and output from nano-chip can be detected.

FIG. 9 shows the signal processing block diagrams according to thisinvention wherein same numerals represents the similar parts shown inFIG. 8, so that similar explanation is omitted here. According to thisinvention, Electrical-processing circuit 28, shown in FIG. 9, compriseswith electrical signal integration circuit 66, filtering andsample-counter circuit 68 to remove electrical noise, and a read-outcircuit 70 to store the data. Each of these blocks 66, 68, and 70 areexplained in details in FIGS. 10, 11, and 12. The electrical signaloutputs from this signal-processing unit 28 are reference signal 29(a)and signal 29(b) after specimen absorbed by the nano-chip. In absence ofspecimen absorption, the electrical signals 29(a) and 29(b) are thesame.

FIG. 10A shows the integrated circuit block in details, of the blockdiagrams, as shown in FIG. 9, and FIGS. 10B and 10C are the waveforms ofpoint A and B, as shown in FIG. 10A, according to this invention whereinsame numerals represent the similar parts shown in FIGS. 8 and 9, sothat similar explanation is omitted here. The electrical integrationcircuit 66 means as shown in FIG. 10 is a part of the electricalprocessing circuits 28. According to this invention, electricalintegration circuit 66 means comprises with transimpedance amplifier(TIA) 72, two sets of switches 77 and 78, a an analog memory 74 to storethe reference value as reference voltage 76, and two sets of integratorcircuits 73(a) and 79(a), two sets of comparators 73(b) and 79(b), andone differentiator 82.

According to this invention, the signal 26 input to TIA 72 of theintegrated circuit 66 to have the proportional voltage output V_(in).Initially, the switch S1 77 is on and switch S2 78 is off. While theSwitch S1 77 is on, the proportional voltage output Vin is directly feedthrough the analog memory 74 to store the initial voltage as thereference voltage 76 (output of analog memory 74). Noted here that thereference voltage V_(ref) can be either same or greater than that theproportional voltage output V_(in). The reference voltage V_(ref) isintegrated by the integrator 73(a) and its output is directly feed tothe comparator 73(b) whose other input is set to V_(ref). While theintegrator 73(a) output is reached to V_(ref), the comparator 73(b)output will reset the Integrator 73(a). The resultant waveform 63 fromcomparator 73(b) is saw-tooth type waveforms as shown in FIG. 10B forthe point A of FIG. 10A. The resultant waveform 63 is acted as theoutput of V_(ref) and mentioned here as V_(out1), while there is noabsorption of the specimen in the nano-chip explained earlier. As soonas integration for the pre-desired cycle (explained later in FIG. 10B)is completed, the switch S1 77 is turned to OFF and at the same time S278 is turned on and the output from the TIA 72 is directly feed to thedifferentiator 82 whose other input is output 76 from Analog memory 74.The differences 80, output from the differentiator 82 is similarly feedto the integrator 79(a), whose output is again feed to the comparator79(b). Noted here that other input to the comparator 79(b) is V_(ref).The resultant waveform 65 is also saw-tooth like waveform (mentioned asV_(out2)), as shown in FIG. 10C (at point B) and it can be generated bythe reset 81, as mentioned earlier. The differences between two sets ofcircuits as shown in FIG. 10A after and before switch S1 77 ON and OFFis that they process the signals without and specimen absorption,respectively. According to this invention, the output waveforms 63 and65 comprises with stream of saw-tooth like waveforms 83(a) and 83(b)which can be processed for captured explained later in FIG. 12.

FIG. 11A is an example of the schematic showing the Filter-circuit ofprocessing circuits 28 blocks shown in FIG. 9, according to thisinvention wherein the similar numerals represent the same parts as shownin FIGS. 10A, 10B, and 10C. The filter & sample-counter means block 68is a part of the electrical processing circuit 28 and comprises with ancommon clock signal 84, two sets of filters 85(a) and 85(b), and twosets of sample counters 86(a) and 86(b). Two sets are used to processthe outputs 63 and 65 separately. The filter & sample-counter block 68is used to convert the waveforms achieved from the reference value 63(with no specimen present) and new value 65 (with specimen present). InFIG. 11A, “Filter” blocks 85(a) and (85(b) are used to avoid glitches ofthe signals generated from the integrated circuit, explained in FIG.10A. The “Sampler & Counter” blocks 86(a) and 86(b) can be used tocompare the values of “Filter” blocks 85(a) and 85(b) to the values fromthe integrated circuit 66, in FIG. 10A.

FIGS. 118 and 11C show the output signals 63 and 65 with capture time atdifferent points for example at 87(a) and 87(b). These two signals 63and 65 will provide us with two saw-tooth based waveforms with differentslopes; represent the output signal amplitude (not shown here). They canhave the different time intervals for example, t₁, t₂, t₃- - - t_(n),total of ‘tn’ for output signal 63 (no specimen absorption) and t₁′,t₂′, - - - t_(n), total of the same time ‘tn’ for output signal 65 (withspecimen absorption) for analysis. Several techniques can be used toanalyze the waveforms to detect the concentration of the specimenabsorbed. According to this invention, certain capture point 87(a) and87(b) in waveforms 63 and 65, respectively, can be used at differentintervals and different amplitude to avoid the noise, if any, presencein the signals. The output signals from sampler and counter circuits86(a) and 86(b) after capturing can be the stream of the digital signals88 as shown FIG. 11B, and 88 and 29(b) as shown in FIG. 11A. Thecorresponding analog signals output from filter circuits 85(a) and 85(b)is an integrated signals 90(a) and 90(b), respectively.

FIG. 12 is the schematic showing an example of read-out circuit, a partof processing circuits 28 blocks shown in FIG. 9, according to thisinvention wherein the similar numerals represent the same parts as shownin FIGS. 10A and 11A. The read-out circuit means 70 shown in FIG. 12averages the waveforms and then stores in the memory. Signals 88received for reference value, will be stored into a read-out circuit 70,shown in FIG. 12, which is a part of the electrical processing circuit28, as shown in FIG. 9. Read-out circuit 70 could be one for each of thereference value or specimen value to store (not shown here).Alternatively, one read-out circuit for reference value store can alsobe used which is used in FIG. 9 as for example. Any number of bits canbe used for read-out circuit. As for example, a 12-bit circuit isconsidered in FIG. 12. This read-out circuit 70 can be fabricatedutilizing standard CMOS process technology. For example, this read-outcircuit can be fabricating with standard 350 nm, 3.3 volt, andthin-oxide digital CMOS process geometry or less. The data will come toeach bit (1-12) 91 of pass-gate transistor for storage. After the datais stored in the transistor, read-out port 92 will give us the storedvalues as outputs 29(a) for the reference value 88. This circuit willhave a ‘reset’ line 93, so that we can flush out the older data, ifnecessary. This circuit can be single transistor CMOS, p and n-channeltransistor CMOS, or capacitive based circuit, which can be fabricatedusing conventional CMOS technology. FIG. 13 is the schematics showingthe block diagrams of the monitoring system, according to the invention,wherein the same numerals represent the same parts, explained in FIGS.9, 10A, 11A, and 12, so that repeated explanation is omitted here. Thismonitoring system 30 comprise of several blocks such as: “Divider for(1-Power Factor)” block 94, Digital Signal Processing (DSP) unit 96,Digital to Analog Conversion (DAC) block 100, Radio Frequency (RF)Transceiver block 102, Concentration Display block 104 and remoteStation block 106 to monitor the analyzed value. The RF unit 102 is forremotely monitor the specimen.

The signals 29(a) and 29(b) from the processing circuit unit 28 feed tothe divider circuit 94 to calculate (1-power factor), as shown in EQ. 9,and its resultant output signal 95 feeds to the n-bit digitalsignal-processing unit 96, where n is the number of the bit. Otherinputs to DSP unit are known parameters such as reference concentration(mentioned as background concentration of the specimen, if any), otherrequired refractive indices related to the nano-chips, explainedearlier. The DSP unit 96 is commercially available from various vendorsor the unit can be fabricated with standard CMOS technology, dependingon the specification criterion. This DSP unit 96 includes a systemcontroller for coordination. The system controller of the DSP unit 96may be chosen to be an n-bit RISC/CISC-type processor, which iscommercially available by various vendors such as Texas Instrument,INtel. The processor and system controller may share a memory forprogram and data storage.

Output signals of the DSP block 96, which are digital signals, can beconverted into analog by using the “DAC” block 100. Output signals fromthe “DAC” block 100 can be transmitted through the “RF Transceiver”block 102. Signals from block 102 may be wirelessly monitored from theremote “Station” block 106 by using standard wireless protocol such asBLUETOOTH, 802.11a/b/g protocol or other proprietary protocols. Thesystem can be embed with the standard (display) based monitoring unit104 by feeding a part of DSP signal to the monitoring unit 104 tomonitor in real time the concentration of the specimen.

According to this invention, whole processing unit can be made into asingle chip and can be fabricated using standard IC technology.Alternatively, whole processing unit can be also build hybridly.

According to this invention, FIGS. 9 to 13 explain the signal-processingunit to monitor the specimen concentration. This is given for exampleonly. Various signal processing ways (utilizing similar idea as shown inFIGS. 9-13) can be used to monitor the specimen concentration. Forexample, alternatively, single switch (single pole double through) canbe used instead of using two switches (S1 and S2), explained in FIG.10A. In addition, alternatively analog divider (not shown here) can alsobe used instead of using digital divider 94, (shown in FIG. 13).Additional analog to digital converter may require converting theresultant analog signal after dividing by divider (not shown here).

According to this current invention, any microprocessor, FPGA, or ASICcircuit can be used instead of DSP to perform the DSP functionality.These are available from the commercial vendors. For example,microprocessor can be obtained from Intel, FPGA from Actel and Xilinx,and ASIC circuit could be custom designed for required functionality,and it can be off-shore design and manufacturing.

According to this invention, alternatively the read-out memory circuitcan be made based on capacitive load. FIG. 14 shows a schematic diagramof an alternative read-out circuit, wherein same numerals represent thesame parts as shown in FIG. 12, so that repeated explanation is omittedhere. The difference of read-out circuit as shown in FIG. 12 is thatread-out circuit 118 in FIG. 14 is based on capacitive load 110 and a 1to 1 switch 112. The advantages of using this circuit are: low area andlow power. At least one 1 to 1 switch 112 and at least one capacitiveload 110 can be used for single bit of memory. Input signal 88 can bestored by each capacitor 110 and the stored values can be as outputsignal 29(a) as a reference (initial) value.

According to this invention, the signal processing unit and themonitoring units both as shown in FIGS. 9 to 14 can be fabricatedmonolithically into a single chip. Standard Si-CMOS technology can beused for fabricating the signal processing and monitoring chip either insingle chip form or multiple chips. The geometry of the silicon-CMOStechnology can be ranged from 0.35 μm 20 nm or less. The divider 94 canbe designed in different ways for example carry-save, Boolean, binarytype or synthesis library specific type, depending on the desiredperformance and area.

FIG. 15 shows a schematic of the nano-sensing detection system unitaccording to this invention wherein the same numerals represent the sameparts as explained in FIGS. 2 to 14, so that repeated explanation isomitted here. The sensing means 120 comprises with at least one laser 12connecting with electrical driver 122 through electrical connection 124,splitter 126, nano-chip 16(a, b, c, d, e), at least one detector 20,signal processing unit 130, connecting with the external power suppliesthrough connection 132, and a common carrier substrate 134. According tothis invention, light 14 having fixed wavelength is made to couple tothe 1×k splitter 126 (where k is the number of splitters which is atleast one) to split the intesity of light 14 into k numbers and made topass through the nano-sensor 16(a, b, c, d and e). Alternatively,according to this invention, the splitter and nano-chip can also bedesigned to operate in broadband light. In that case, the waveguide isto be multi-mode to operate in broad spectrum of light.

The splitter can be designed based on the photonics crystals having rodor holes, arranged periodically to made photonic band gap structure.Both splitter and nano-chips can have the same photonic band gapstructure or different, and they can be fabricated on the commonsubstrate 136. Alternatively, the splitter can be designed based on thehomogeneous (solid) substrate (without photonics crystal) and thenano-chip can be based on photonic crystal base. Again, they can befabricated onto the common substrate 136, or both splitter 126 andnanochip 16(a, b, c, d and e) can be fabricated in separate substrates,and afterwards hybridly packaged onto the common substrate (not shownhere). To detect different types of specimens. For example differentbio-molecules, different types of receptors can be used in thenanochips. The outputs from each nanochip are made to incident to thedetector 20 to convert optical signal into corresponding electricalsignals (not shown here). The electrical signal is processed by the IC130 to determine the concentration of each specimen. The electrical IC130 can be single chip or multiple chip based on the circuit means, asexplained previously from FIGS. 9 to 14. All electrical components canbe made into the single chip. Optical chip comprising with the splitterand the waveguide, and single chip can be packaged on the commonsubstrate 134 to make the small package of dimension below 1″×1″×0.5″(W×L×H). A key feature of this system 120 is that multiple sensors canbe fabricated on a single wafer 136. Utilizing the multiple sensor helpto detect multiple specimens at the same time. For example, one sensorcan detect chemical agent sensor, the second can be a biomoleculesensor, and the third can be a biological cell detector, and so on.Other example could be a single sensor unit can detect different gasesor different types of bio-molecules simultaneously in real time, and anycombination thereof.

FIG. 16 is a schematic representing the small form-factor sensor system,according to this invention, wherein the same numerals represent thesame parts, as explained in FIGS. 2 to 7 and 15, so that repeatedexplanation is omitted here. The small form factor sensor system 138comprises with two parts wherein first part is a passive section of thesystem and comprises with sample handler 140, two waveguides 142(a) and142(b) for incoming and outgoing optical signals 14 and 18,respectively, and a common substrate 144, and the second part is anactive section of the system and it comprises with carrier substrate146, laser 12, laser driver 122, detector 20, preamplifier 148, signalprocessing integrator circuit 150, and electrical connection 152.

According to this invention, specimen 154(a) is made to pass through theinlet 156(a) of the specimen handler 140 and pass out the specimen154(b) from the outlet 156(b). The passive section of the sensor system138 is designed in a way that a portion of its internal section is madeto expose to the nanochip 16 to make enough contact of the specimenwhile passing through this specimen handler 140. The optical signal 14is made to propagate through the nanochip 16 via waveguides 142(a) and142(b) used for guiding the signals on the passive section of nano-chip16. For simplicity in handling and also for the purpose of reusage ofthe sensor system for long time, the passive section can be a separatesection apart from the active section, and can be replaceable and easilystackable to the active section. Alternatively, both passive and activesections could be single section attached permanently. In FIG. 16, anexample of a small form-factor sensor system containing a singlenano-chip 16 is shown for simplicity in drawing. This can cover also form-number of sensors containing in passive section of the sensor system(not shown here) for m-number of specimens detection. In that case, atleast one specimen handler can be used and each nano-chip can have withsame or different receptors.

According to this invention, the active section of the sensor system 138has signal transmitting section, OE (optical to electrical conversion),and signal processing units (not shown separately). Transmitting sectioncomprises with the laser 12 and driver 122, OE unit comprises withdetector 20 and preamplifier 148, and signal processing unit comprisingwith a chip 150 for further signal processing and monitoring. The signalprocessing chip 150 contains pre-processing unit, post processing, andmonitoring units, explained earlier in FIGS. 9 to 14. Transmitting, OE,and signal processing units are placed on the carrier substrate 146 andthey can be hybridly integrated on carrier substrate 146 or fabricatedmonolithically as single chip. The carrier substrate 146 has the groove158, housed appropriate to the passive section holding. Under operation,both waveguides 142(a) and 142(b) are coupled to the laser 12 anddetector 20, respectively to transmit and receive the signals 14 and 18to and away from the nano-chip. Source (e.g. laser diode or lightemitting diode) 12 with specific wavelength or ranges of wavelength,appropriate to the refractive index of the nanochip 16 can be used andit can be electrically drived by the driver circuit 122. The OE sectionhas the detector 20, having high sensitivity to the source light, can beused to convert the optical signal to electrical. The detector signal isamplified by the pre-amplifier 148 and processed by the chip 150 forpost processing and monitoring the concentration of the specimen. Theelectrical connection 152 connects all electrical components to theexternal power supplies (not shown here). According to this invention,transmitter section, OE section, and signal processing section can befabricated into a single chip utilizing the standard IC technology.Alternatively, each component in active section could be a separatecomponent, hybridly integrated on the substrate (e.g. 146).

According to this invention, the nano-chip described from FIGS. 3 to 7and FIGS. 14 and 15, can be fabricated using any kind of substrateswhich cover, semiconductor, polymer, ceramic, exhibiting opticalproperties. Semiconductor cover Si, III-V or II-VI based compoundsemiconductors. The rods or holes, periodically arranged insidesubstrate and/or in waveguide to form the photonic crystal structure,can be made by utilizing standard wet or dry-etching process frequentlyusing in IC manufacturing. Alternatively, electrochemical orphoto-electro-chemical etching process can also be used to create theholes inside the substrate. According to this, alternatively air-spheresinside can also be used forming photonic crystal based nano-chip, andthey can be made by conventional electrochemical process. For example,large scale of air-spheres in silicon, strong variation of the diameterwith a length of the lattice constant can be made usingphoto-electro-chemical process for crating photonic crystal structurefor the nanochip. Alternatively, porous material (semiconductor,insulator, polymer, or metal) having pores can also be used forfabricating nanochip. The waveguide and the substrate carrying thewaveguide could be same kind of material or different material.Alternatively, nanochip can also be made from the combination of thenanoparticles deposited or synthesized on the substrate arranged inperiodically.

Alternatively, according to this invention, the nanometer sized rods,wire or tubes can also be made from the carbon type materials(semiconductor, insulators, or metal like performances) such as carbonnano-tubes, which could be single, or multiple layered. They can be madeusing standard growth process for example, MOCVD, MBE, or standardepitaxial growth. According to this invention, the self-assembledprocess can also be used to make wires, rods, or tubes and their relatedpn-junction to increase the junction area. These tubes can be grown onthe semiconductors (under same group or others), polymers, or insulator.Alternatively, according to this invention, these rods, wire, or tubes,can be transferred to the foreign substrate or to the layer of foreignsubstrate acting as a common substrate for waveguide for nano-chip. Theforeign substrate or the layer of material can be any semiconductor suchas Si, Ge, InP, GaAs, GaN, ZnS, CdTe, CdS, ZnCdTe, HgCdTe, etc. Thesubstrate can cover also all kinds of polymers or ceramics such as AlN,Silicon-oxide etc. The material can be conductive or non-conductive.

According to this invention, different substrates can be used for makingsensing device as shown in FIGS. 14 and 15. For example, carriersubstrate 134 and common substrate 136 for the splitter and nanochip canbe same or both can be different substrate, in hybrid integratedtogether. Alternatively, the splitter used for the multiple nanochip canbe fabricated from the separate substrate and integrated on the carriersubstrate 134. As a carrier substrate, substrate made of any kind ofmaterial such as semiconductor, ceramic, metal, or polymer can be used.

According to this invention, concentration measurement by determiningthe power factor is explained here. This nanochip based on photonicscrystal can also detect the concentration by other methods, such asmeasuring the fringe-pattern by using of CCD camera and laser beamanalyzer, or absorption spectrum of the optical output by spectroscopy.The concentration and type of the specimen can be known by comparingwith the reference pattern for the case fringe pattern technique, and bycomparing intensity and chemical absorption for the case of absorptionspectrum technique. Turning now to FIG. 17a-g , the chip made fromphotonic crystal (PC) structure (herein after mentioned as photoniccrystal coupled waveguide as “PC-W”) can be fabricated in a number ofways. For example, this description will use Silicon Nitride (SiNx)based photonic crystal structures which have a refractive index of1.5-2.0. FIG. 17 summarizes the procedure for preparing SiNx PC-Wstructure. A fused silica substrate 200 may be used as the commonsubstrate to integrate multiple PC-W sensors. In FIG. 17a , thefunctional SiNx material 201 is deposited either using PECVD or LPCVD.In FIG. 17b , photoresist layer 202 is deposited on the SiNx. In FIG.17c , photoresist layer 202 is lithographically patterned followed by,in FIG. 17d , the deposition of a thin layer of chrome 203 to serve as amask for subsequent pattern transfer of the PC-W holes. With theresidual photoresist removed via acetone liftoff, in FIG. 17e , Cr maskon the remaining surface defines the areas that are to be etched in SiNxlayer using anisotropic NF₃ dry etch, as shown in FIG. 17f . Theremaining chrome layer is then removed in FIG. 17g . The structure shownin FIGS. 17a-g are intended to show a cross-sectional view of the chipmade from photonic crystal structure for bio-agents diagnosis.

The materials discussed above are, however, merely an example. Othermaterial systems can also be used, for example, when desiring formationof a disposable test strip. In such a case, microfluidics based bloodplasma filtration unit coupled with PC-W sensing platform may beprovided as disposable plastic test strips. To keep the material andfabrication cost down for fabricating plastic based PC-W sensors andblood plasma filtration unit in a single microfluidic channel, replicamolding procedure provides a low-cost alternative.

In addition to the PC-W structural design, surface treatment tocovalently conjugate bioreceptors is a part of the sensor design andoptimization. The key parameters of surface treatments that influencethe biosensor performance include the orientation and surface coverageof the conjugated bioreceptors. Due to the glass-like surfaces of theSiNx and fused silica all-dielectric photonic crystal, typical surfacetreatment techniques from biochemistry such as chemical etchingtechniques, vapor or plasma deposition, and the formation ofself-assembled monolayers (SAMs) can be utilized for immobilizingbioreceptor layer.

Silicon Nitride (SiNx) structure surface can be modified by using one ofthe two SAM organosilanes, i.e. 3-(2-aminoethylamino)propyltrimethoxysilane (for NH₂ grafting), or 10-(Carbomethoxy)decyldimethylchlorosilane (for COOH grafting after activation with HCl). Toperform the NH₂ silanisation the samples need to be placed in a solutioncontaining methanol and acetic acid glacial, eventually adding theC₈H₂₂N₂O₃Si. For COOH grafting, the samples need to be immersed in asolution of C₁₄H₂₉ClO₂Si dissolved in a mixture of CCl₄ and n-C₇H₁₆followed by final immersion of the samples in HCl solution. Aftersuccessful silanization of the surface, the bioreceptors may beselectively immobilized through diffusion onto the sensor surface byplacing several small drops of bioreceptors directly above therespective PC-W sensor units. The samples then need to be incubated andthoroughly cleaned to remove any unbounded bioreceptors onto thesurface. To passivate the sensor surface from non-specific biomoleculebinding, detergent blockers such as Tween-20, Triton X-100 or proteinblockers such as Bovine serum albumin (BSA) may be used.

While it has previously already been mentioned that the aboveembodiments can be used to identify any number of biomolecules, a fewspecific applications are also beneficial. Specifically, an embodimentfor sensing pathogens (such as Hepatitis B) or HIV can be created. FIG.18 shows one such preferred embodiment, according to this invention. Asshown in the FIG. 18, when using the present invention to test forspecific molecules within the human body, some additions andmodifications to the structure are favorable. FIG. 18 shows, forexample, where a portion of the device, 302, is removable from the mainbody 300. Here, a blood sample enters the inlet 304 on the test strip302, passes through a blood filtration system 306, the PC-W sensingplatform 308, and then exits the strip through outlet 310. The laser andlaser source 312 are placed on the main body 300 in such a way as todirect the laser into waveguide 314 located on the test strip 302. Thelaser signal then travels through the PC-W sensing platform 308, exitsout of waveguide 316, and is sensed by the detector 318 on the main bodyof the device. The integrated circuit 320 converts the laser signal toan electrical signal, analyzes it, and displays the result in thedisplay screen 322. Connections between the various components are notshown in FIG. 18.

FIG. 18 shows an additional component from those embodiments discussedpreviously (such as that shown in FIG. 16), known as a blood filtrationsystem 306. During measurement, a small volume of blood sample (e.g atleast a drop) needs to be flow into the microfluidic channel (notshown). The microfluidic channel will include a filtration chip forextracting plasma from the whole blood sample. The filtration chipcomprises microfluidic channels that use hydrodynamic forces to separatehuman plasma from blood cells. Individual filtration unit (not shownhere as part of the blood filteration unit 306) comprises an inlet thatis reduced by approximately 20 times to a small constrictor channel.This channel opens out to a larger output channel with a relativelysmall lateral channel for the collection of plasma. Studies have shownthat this type of filtration unit was capable of removing 97.05±0.5percentages of cells at 200 μl min⁻¹ flowrate. The plasma from thefiltration chip flows onto the PC-W sensing units through a dedicatedchannel allowing the target biomolecules to bind to the bioreceptors.Before the optical measurement, a stringent cleaning procedure using abuffer solution may be used to eliminate non-specific biomoleculeinteractions since they can negatively influence the output opticalsignal. The two waveguides, 314 and 316, attached to the test stripfacilitate the transport of the optical signals from the laser source tothe PC-W sensing arrays and from there into the signal processing unitfor data analysis. A small display unit 322 will be included fordisplaying the test results real-time. The integrated point-of-carediagnostic platform can be powered by conventional Li-ion batteries.

FIG. 19 in included as an example of a more detailed diagram from thegeneralized FIG. 18, according to this invention. It is included merelyas an additional aid to visualize possible embodiments, and is notintended to be limiting the present invention.

Pathogen-Sensing

The embodiment may be designed to have arrays of independent biosensingunits coupled onto the PC-W platform, providing parallel detection ofmultiple biomarkers. While this is beneficial for all types ofdetection, this is especially beneficial when detecting certainpathogens, such as HBV, which have multiple detectable markers. NumerousHBV markers include hepatitis B surface antigen (HBsAg), hepatitis Bsurface antibody (anti-HBs), hepatitis B e antigen (HBeAg), hepatitis Be antibody (anti-HBe), hepatitis B core antigen (HBcAg), and hepatitis Bcore antibody (anti-HBc). For maximum accuracy, test strips may bedesigned to detect approximately five different HBV markers.

Although this embodiment specifically utilizes a blood filtrationsystem, alternatively the embodiment might be designed to detectbiomarkers in saliva, other body tissue, or other body fluid. If this isthe case, then the blood filtration system may be omitted or replacedwith a different type of filtration system. For example, due to theviscosity of saliva, movement through a simple sample inlet may bedifficult. A microfluidic system may be used to aid the movement of thesample into the PC-W sensor platform, wherein a drop of fluid may ableto flow by capillary force.

HIV-Sensing

Another alternate embodiment is one which is designed to detect HIV. Thetypical HIV diagnosis tests are based on the detection of antibodiesproduced by the human body in response to the HIV infection. Forclinical laboratory-based HIV screenings, enzyme-linked immunosorbentassay (ELISA) is the first test conducted to look for HIV antibodies. Ifthe test indicates the presence of HIV antibodies (positive), the testis again repeated to confirm the diagnosis. In the case of secondpositive ELISA result, a complementary test called Western blot isdeemed necessary to confirm the diagnosis since it is more adept atdistinguishing HIV antibodies from other antibodies present in theblood. The need for advanced technical skills and higher operating costslimits the use of Western Blot only to a confirmatory test. Althoughassay based techniques such as ELISA and Western Blot provide diagnosticresults with high accuracy, their major shortcoming is the high numberof false negative diagnostic results during the “window period. The 3-12weeks period between the onset of HIV infection and the appearance ofmeasurable antibodies to HIV seroconversion is known as the windowperiod. Among high-risk populations, the current antibody tests areshown to miss about 10 percent of acute HIV infections by showingantibody-negative. Alternate HIV testing methodologies involve thedetection of HIV antigen, or nucleic acid amplification testing (NAAT).Antigen testing looks for soluble p24 antigen, presumably followingviral replication, and does not specifically identify live virus. Thelevel of p24 antigen increases significantly during the initial phasesof the infection, then declines to undetectable levels as they bind toHIV antibodies [Christine C. Ginocchio, HIV-1 Viral Load Testing Methodsand Clinical Applications, laboratory medicine (2001), 32 (3), 142-152).Since the estimated average time from detection of antigen to detectionof HIV antibodies is 6 days and not all recently infected persons havedetectable levels of p24 antigen, HIV diagnosis using stand alone p24antigen test is strongly discouraged, nucleic acid amplification testing(NAAT) procedure widely used for screening donated blood detects one ormore of several target sequences located in specific HIV genes and canprovide diagnosis much earlier than the antibody test. However, thedrawbacks to NAAT testing include: need for sophisticatedinstrumentation, high operating costs and unaffordable in remote andnon-laboratory settings. Therefore, there is still a strong need todevelop a cost effective, laboratory-free diagnostic system that candetect acute HIV-1 in-house or in-remote settings of developingcountries without the need for trained technicians or advancedfacilities.

As described above, currently, HIV diagnosis in general is costly, andadditionally inaccurate during the initial window after infection, andmost importantly takes long time to get diagnosis results.

According to this invention, this embodiment is a diagnostic system thatcan diagnose HIV infection within the window period based on paralleldetection of two characteristic HIV-1 biomarkers, i.e. HIV-1 Tat proteinand HIV-1 antibodies (here in referred as antibodies). Tat protein is aprimary HIV gene that regulates the early stage replication of HIV,whereas antibodies are produced by the body in order to combat theassortment of proteins produced by HIV infection. Bioreceptors arebiomolecules attached to the transducer surface based on their highspecificity towards target specimen to form a functional sensor.According to this invention, bioreceptors are used for TAT proteindetection which provide the information on even before window periodcondition of the patient.

The multi-analyte diagnostic platform is based on biosensing deviceplatform, as described previously in FIGS. 3 to 7 and also FIGS. 15, 16,18, and 19 for measuring the miniscule refractive index changes when thebiomarkers in the sample bind to the characteristic bioreceptors. Theintegration of blood plasma separation, optical biosensing and dataprocessing assembly on the same platform makes possible the developmentof a sample-to-answer system with automated data analysis providing arapid diagnostic readout (<30 min). In addition, the use of robustbioreceptors that have high storage stability at ambient conditionsoffers the potential to use the proposed diagnostic system in remotesettings without cold storage facilities.

Structurally, the embodiment for detecting HIV may be very similar tothat of the embodiment for detecting pathogens. It may utilize the samedisposable plastic test strips and blood filtration system, and the onlysignificant difference would be the biomarkers used in the photoniccrystal arrays.

Detection of HIV can be done through detection of two indicators: HIV-1Tat proteins or HIV-1 antibodies. For the detection of HIV-1 Tatprotein, as shown in FIG. 20A, one may use an aptamer that binds to theTat protein with two orders of magnitude greater (133-fold) affinityover the TAR RNA of HIV-1. Recently developed two aptamers: Probeaptamers-RNA^(Tat) and aptamer-derived second strand(5′-UCGGUCGAUCGCUUCAUAA-3′-NH₂ and 5′-GAAGCUUGAUCCCGAA-3′ respectively)may be used to function as bioreceptors for the detection of real HIV-1Tat protein extracted from blood. At first, the probe RNA^(Tat) aptamersare covalently attached to the photonic crystal surface of the PC-Wsensing platform. Once exposed to a blood sample, any present HIV-1 TATproteins bind to the probe aptamers along with aptamer-derived secondstrands, thereby forming duplex structures. The high storage stabilityof aptamers even at ambient conditions can be used to develop diagnosticsystems that do not require refrigeration to maintain their detectionperformance. Alternatively, a simple annealing step at 70° C. for 3 minmay be used to recover the functional activity of immobilized aptamersupto 90%.

Alternately, on the other hand, for the detection of HIV-1 antibodies,HIV proteins called antigens, shown in FIG. 20B, may be used asbioreceptors. The antigens are covalently attached to the biochipssensing platform (as described previously). Once exposed to a bloodsample, any present HIV-1 antibodies bind to the antigens.

For maximum accuracy in testing, the embodiment may be designed,similarly to the HBV detector, with multiple independent parallelbiosensing units, wherein each unit detects a different biomarker.

Whereas many alterations and modifications of the present invention willno doubt become apparent to a person of ordinary skill in the art afterhaving read the foregoing description, it is to be understood that theparticular embodiments shown and described by way of illustration are inno way intended to be considered limiting. Therefore, reference to thedetails of the preferred embodiments is not intended to limit theirscope. Although the invention has been described with respect tospecific embodiment for complete and clear disclosure, the appendedclaims are not to be thus limited but are to be construed as embodyingall modification and alternative constructions that may be occurred toone skilled in the art which fairly fall within the basic teaching hereis set forth.

The present invention is expected to be found practically use in theindustrial, commercial, and bio-medical application. Using of suchsensor device will help to detect very low level concentration (in ppblevel) of gases, requiring in industrial application. This sensordevices is not limited to use in chemical gas, bio-molecule gas only,this can also be used in biological cell detection and their low levelconcentration measurement. The main advantages of this invention arethat detection and concentration of multiple specimens at a real timecan be possible. Multiple specimens can be multiple gases, multiplebio-molecules, or multiple bio-logical cells, or their combinations.

What is claimed is:
 1. A sensing device comprising: a nanochip having awaveguide with a core and a cladding, said cladding having a periodicdielectric system that forms a photonic bandgap; a light sourceconfigured to send optical signals through the core of said waveguide; aplurality of receptors for interacting with a specimen to be sensed,said receptors disposed in the periodic dielectric system of thecladding; a detector for converting optical signals sent through thecore of the waveguide into electrical signals; at least one electricalprocessing circuit for processing electrical signals received from thedetector, said electrical processing circuit configured to output afirst signal and a second signal, wherein the first signal correspondsto the intensity of the optical signal passing through the waveguidewithout specimen interaction with the receptors, and the second signalcorresponds to the intensity of an optical signal passing through thewaveguide with specimen interaction with the receptors; at least onemonitoring system for determining the concentration of a specimen basedon signals received from the electrical processing circuit, saidmonitoring system configured to calculate a ratio of the first signaland the second signal, correlate said ratio to a change in effectiverefractive index of the cladding resulting from specimen interactionwith the receptors, and correlate the change in effective refractiveindex to the concentration of the specimen; at least one display unit;at least one sample handling system connected to said nanochip, saidsample handling system having an inlet and outlet for said specimen topass through and at least one microfluidics system.
 2. A method offabricating the cladding of claim 1, comprising: depositing a layer ofsilicon nitride on a silicon substrate using PECVD or LPCVD; depositinga layer of photoresist on said layer of silicon nitride; patterning saidlayer of photoresist using lithography, thereby exposing sections ofsaid layer of silicon nitride; depositing a mask layer on said layer ofphotoresist and said exposed sections of said layer of silicon nitride;removing said layer of photoresist using acetone liftoff; patterningsaid layer of silicon nitride using dry etching; and removing said masklayer.
 3. A sensing device comprising: a main body, said main bodyfurther comprising: a substrate; a light source; a detector forconverting optical signals into electrical signals; at least oneelectrical processing circuit for processing electrical signals receivedfrom the detector, said electrical processing circuit configured tooutput a first signal and a second signal, wherein the first signalcorresponds to the intensity of the optical signal passing through thewaveguide without specimen interaction with the receptors, and thesecond signal corresponds to the intensity of an optical signal passingthrough the waveguide with specimen interaction with the receptors; atleast one monitoring system for determining the concentration of aspecimen based on signals received from the electrical processingcircuit, said monitoring system configured to calculate a ratio of thefirst signal and the second signal, correlate said ratio to a change ineffective refractive index of the cladding resulting from specimeninteraction with the receptors, and correlate the change in effectiverefractive index to the concentration of the specimen; and at least onedisplay unit, and a removable section, said removable sectioncomprising: a nanochip having a first waveguide with a core and acladding, said cladding having a periodic dielectric system that forms aphotonic bandgap; a second waveguide for guiding optical signals fromsaid light source to said nanochip; a third waveguide for guidingoptical signals from said nanochip to said detector; an inlet forspecimens; a microfluidic system for allowing specimen to move easilyfrom said inlet to said nanochip; an outlet for specimens; and aplurality of receptors for interacting with a specimen to be sensed,said receptors disposed in the periodic dielectric system of thecladding.
 4. The sensing device of claim 3, wherein said plurality ofreceptors are chosen for binding with HBsAg, anti-HBs, HBeAg, anti-HBe,HBcAg, anti-HBc, or a combination thereof.
 5. The sensing device ofclaim 3 comprising a plurality of nanochips, and a plurality ofdetectors, wherein each said nanochip utilizes a different type ofreceptors.
 6. The sensing device of claim 3, wherein the electricalprocessing circuit comprises: an electrical signal integration circuitfor integrating electrical signals received from the detector over time;a filter and sample-counter circuit for removing electrical noise fromthe signals received from the electrical signal integration circuit andgenerating corresponding digital signals; and a read out circuit forstoring digital signals received from the filter and sample-countercircuit.
 7. The sensing device of claim 6, wherein the electrical signalintegration circuit comprises: a transimpedance amplifier (TIA); a firstswitch and a second switch; an analog memory; a first integrator circuitand a second integrator circuit; a first comparator and a secondcomparator; and a differentiator, wherein: the TIA feeds through thefirst switch, through the analog memory, to the first integratorcircuit; the first integrator circuit feeds to the first comparator,which is reset back to the first integrator circuit; the firstcomparator feeds into the monitoring system; the TIA feeds through thesecond switch to the differentiator; the analog memory feeds to thedifferentiator; the differentiator feeds to the second integratorcircuit; the second integrator circuit feeds to the second comparator,which is reset back to the second integrator circuit; and the secondcomparator feeds to said monitoring system.
 8. The sensing device ofclaim 7, wherein the filter and sample-counter circuit comprises: acommon clock for generating a clock signal; a first filter for filteringsignals received from the first comparator; a second filter forfiltering signals received from the second comparator; a first samplecounter for comparing signals received from the first comparator tosignals received from the first filter; and a second sample counter forcomparing signals received from the second comparator to signalsreceived from the second filter.
 9. The sensing device of claim 3,wherein the monitoring system comprises: a digital divider circuit forcalculating said ratio; and an n-bit digital signal processing (DSP)unit for determining concentration of the specimen based on said ratio.10. The sensing device of claim 3, further comprising a preamplifier foramplifying signals received from the detector.
 11. A sensing devicecomprising: a main body, said main body further comprising: a substrate;a light source; a detector for converting optical signals intoelectrical signals; at least one electrical processing circuit forprocessing electrical signals received from the detector, saidelectrical processing circuit configured to output a first signal and asecond signal, wherein the first signal corresponds to the intensity ofthe optical signal passing through the waveguide without specimeninteraction with the receptors, and the second signal corresponds to theintensity of an optical signal passing through the waveguide withspecimen interaction with the receptors; at least one monitoring systemfor determining the concentration of a specimen based on signalsreceived from the electrical processing circuit, said monitoring systemconfigured to calculate a ratio of the first signal and the secondsignal, correlate said ratio to a change in effective refractive indexof the cladding resulting from specimen interaction with the receptors,and correlate the change in effective refractive index to theconcentration of the specimen; and at least one display unit, and aremovable section, said removable section comprising: a nanochip havinga first waveguide with a core and a cladding, said cladding having aperiodic dielectric system that forms a photonic bandgap; a secondwaveguide for guiding optical signals from said light source to saidnanochip; a third waveguide for guiding optical signals from saidnanochip to said detector; an inlet for specimens; a blood filtrationsystem for separating plasma, wherein said blood filtration system isconfigured to allow the separated plasma to contact said nanochip; anoutlet for specimens; and a plurality of receptors for interacting witha specimen to be sensed, said receptors disposed in the periodicdielectric system of the cladding.
 12. The sensing device of claim 11,wherein said plurality of receptors are HIV-1 aptamers or antigenschosen for binding with HIV-1 TAT protein.
 13. The sensing device ofclaim 11, wherein said aptamer are selected from the group consisting ofaptamers-RNATat, aptamer-derived second strand(5′-UCGGUCGAUCGCUUCAUAA-3′-NH2 and 5′-GAAGCUUGAUCCCGAA-3′) andcombination thereof.
 14. The sensing device of claim 11, comprising a atleast two nanochips and at least two detectors, wherein each saidnanochip utilizes a different type of receptor.
 15. The sensing deviceof claim 11, wherein the electrical processing circuit comprises: anelectrical signal integration circuit for integrating electrical signalsreceived from the detector over time; a filter and sample-countercircuit for removing electrical noise from the signals received from theelectrical signal integration circuit and generating correspondingdigital signals; and a read out circuit for storing digital signalsreceived from the filter and sample-counter circuit.
 16. The sensingdevice of claim 11, wherein the electrical signal integration circuitcomprises: a transimpedance amplifier (TIA); a first switch and a secondswitch; an analog memory; a first integrator circuit and a secondintegrator circuit; a first comparator and a second comparator; and adifferentiator, wherein: the TIA feeds through the first switch, throughthe analog memory, to the first integrator circuit; the first integratorcircuit feeds to the first comparator, which is reset back to the firstintegrator circuit; the first comparator feeds into the monitoringsystem; the TIA feeds through the second switch to the differentiator;the analog memory feeds to the differentiator; the differentiator feedsto the second integrator circuit; the second integrator circuit feeds tothe second comparator, which is reset back to the second integratorcircuit; and the second comparator feeds to said monitoring system. 17.The sensing device of claim 12, wherein the filter and sample-countercircuit comprises: a common clock for generating a clock signal; a firstfilter for filtering signals received from the first comparator; asecond filter for filtering signals received from the second comparator;a first sample counter for comparing signals received from the firstcomparator to signals received from the first filter; and a secondsample counter for comparing signals received from the second comparatorto signals received from the second filter.
 18. The sensing device ofclaim 11, wherein the monitoring system comprises: a digital dividercircuit for calculating said ratio; and an n-bit digital signalprocessing (DSP) unit for determining concentration of the specimenbased on said ratio.
 19. The sensing device of claim 11, furthercomprising a preamplifier for amplifying signals received from thedetector.
 20. The sensing device of claim 11, wherein said bloodfiltration system comprises: an inlet channel for inserting a bloodsample, wherein said inlet channel reduces gradually by about 20 timesinto a small constrictor channel; an output channel, wherein said outputchannel is wider than said constrictor channel; and a microfluidicchannel connected laterally to said output channel for collectingseparated plasma.